U.S. patent application number 15/563254 was filed with the patent office on 2018-04-05 for improved process for preparing idelalisib.
The applicant listed for this patent is SYNTHON B.V.. Invention is credited to Libor VYKLICKY, Miroslav ZABADAL.
Application Number | 20180093987 15/563254 |
Document ID | / |
Family ID | 55589898 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180093987 |
Kind Code |
A1 |
VYKLICKY; Libor ; et
al. |
April 5, 2018 |
IMPROVED PROCESS FOR PREPARING IDELALISIB
Abstract
The present invention relates to an improved process for
preparing Idelalisib (1). In this process, acid addition salts of
idelalisamine (2) are useful intermediates for purification
purposes. ##STR00001##
Inventors: |
VYKLICKY; Libor; (Blansko,
CZ) ; ZABADAL; Miroslav; (Blansko, CZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYNTHON B.V. |
Nijmegen |
|
NL |
|
|
Family ID: |
55589898 |
Appl. No.: |
15/563254 |
Filed: |
March 24, 2016 |
PCT Filed: |
March 24, 2016 |
PCT NO: |
PCT/EP2016/056628 |
371 Date: |
September 29, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 63/02 20130101;
C07D 239/91 20130101; B01D 9/005 20130101; C07D 473/34
20130101 |
International
Class: |
C07D 473/34 20060101
C07D473/34; C07D 239/91 20060101 C07D239/91; C07B 63/02 20060101
C07B063/02; B01D 9/00 20060101 B01D009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2015 |
EP |
PCT/EP2015/057007 |
Claims
1. In a process for synthesizing preparing idelalisib of formula
(1) from idelalisamine of formula (2), ##STR00003## the improvement
for which comprises isolating an acid addition salt of
idelalisamine before its chemical conversion to idelalisib.
2. The process of claim 1, wherein the acid in the acid addition
salt of idelalisamine (2) is hydrochloric acid, benzoic acid,
fumaric acid, malonic acid, tartaric acid, ethanesulphonic acid,
p-toluenesulphonic acid or oxalic acid.
3. The process of claim 1, wherein the acid in the addition salt of
idelalisamine is hydrochloric acid.
4. A process which comprises: (a) mixing idelalisamine free base of
formula 2 ##STR00004## with an acid selected from hydrochloric
acid, benzoic acid, fumaric acid, malonic acid, tartaric acid,
ethanesulphonic acid, p-toluenesulphonic acid or oxalic acid, in a
solvent or solvent mixture and (b) isolating the idelalisamine acid
addition salt.
5. A process of claim 4, wherein the mixing of idelalisamine free
base with an appropriate acid of step (a) is performed in a crude
reaction mixture.
6. A process according to claim 5, wherein step (a) is performed in
a solvent or solvent mixture comprising at least one of:
1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl.sub.3, CH.sub.2Cl.sub.2,
Toluene and t-BuOH.
7. A process according to claim 4, wherein step (a) is performed in
2-Me-THF or a solvent mixture comprising 2-Me-THF.
8. A process according to claim 4, wherein step (b) is performed by
crystallising the idelalisamine acid addition salt.
9. A process according to claim 4, which further comprises
purifying said isolated idelalisamine acid addition salt which
comprises the steps of: (i) dissolving the salt in a solvent, and
(ii) inducing crystallisation of the idelalisamine acid addition
salt.
10. The process of claim 9 wherein the solvent in step (i) is
chosen from 1,4-dioxane, EtOAc, THF, 2-Me-THF, CHCl.sub.3,
CH.sub.2Cl.sub.2, Toluene and t-BuOH.
11. The process of claim 9 wherein the solvent in step (i) is
2-Me-THF.
12. An acid addition salt of idelalisamine of formula (2)
##STR00005##
13. The acid addition salt of claim 12, wherein the acid in the
acid addition salt is hydrochloric acid, benzoic acid, fumaric
acid, malonic acid, tartaric acid, ethanesulphonic acid,
p-toluenesulphonic acid or oxalic acid.
14. An acid addition salt of claim 12, wherein the acid in the acid
addition salt is hydrochloric acid.
15. The process according to claim 1 in which the improvement
further comprises purifying said isolated idelalisamine acid
addition salt which comprises the steps of: (i) dissolving the salt
in a solvent, and (ii) inducing crystallisation of the
idelalisamine acid addition salt.
16. The process according to claim 15, wherein the acid in the
addition salt of idelalisamine is hydrochloric acid.
17. The process according to claim 16, wherein said solvent in step
(i) is 2-Me-THF.
Description
BACKGROUND OF THE PRESENT INVENTION
[0001] This invention relates to the preparation of pharmaceuticals
and their intermediates. In particular it relates to an improved
process of preparing idelalisib (1). The process runs via acid
addition salts of idelalisamine (2). Idelalisamine (2) is a late
stage intermediate in the process for preparing idelalisib (1). The
acid addition salts of idelalisamine can be purified easily via
precipitation/crystallization and provide an easy purification
option for a late stage intermediate in the process for preparing
idelalisib (1).
BRIEF DESCRIPTION OF THE PRESENT INVENTION
[0002] Idelalisib (WO2005113556) is a PI3K.delta. inhibitor of
structure (1) and is used for the treatment of patients with
follicular lymphoma, relapsed small lymphocytic lymphoma and
relapsed chronic lymphocytic leukaemia.
[0003] WO2005113556 describes the preparation of idelalisib as
depicted below.
##STR00002##
[0004] The process for preparing idelalisib as described in
WO2005113556 requires chromatographic purification steps for
intermediates (4) and (3), and for idelalisib (1). Chromatographic
purification steps are tedious and expensive process steps on an
industrial scale. Therefore, there is a need for alternative
methods which reduce the number of chromatographic purification
steps in the preparation of idelalisib.
SUMMARY OF THE INVENTION
[0005] The present invention relates to improvement of the overall
efficiency in the process for preparing idelalisib (1) and to the
acid addition salts of idelalisamine (2).
DETAILED DESCRIPTION OF THE INVENTION
[0006] Treatment of idelalisamine (2) with several acids, results
in isolation of the corresponding idelalisamine acid addition salt
in high yield and purity. Also when crude intermediate (3) was used
as starting material for preparing idelalisamine, the acid addition
salt of idelalisamine was isolated in a yield and purity comparable
with the original procedure of WO2005113556. This precipitation
and/or crystallisation of an acid addition salt of idelalisamine
obviates earlier chromatographic steps in the synthesis, thereby
making the process more efficient and less costly. The acid
addition salt of idelalisamine can be used as such in the final
step for preparing idelalisib (1).
[0007] In a first aspect the invention relates to processes for
preparing idelalisib (1) that have acid addition salts of
idelalisamine (2) as intermediate.
[0008] Several acids were tested for their capability to form acid
addition salts with idelalisamine (2) and for their usefulness in
the purification of idelalisamine. Some of the tested acids were
found to produce acid addition salts of idelalisamine that are easy
to precipitate or crystallise, while others formed only oils, very
fine suspensions, or material that liquefied during filtration.
[0009] Best results were achieved using hydrochloric acid, benzoic
acid, oxalic acid, malonic acid, fumaric acid, tartaric acid,
ethanesulphonic acid, or p-toluenesulphonic acid and the acid
addition salts of these acids are the preferred salts of the
current invention. Of these, the acid addition salt of hydrochloric
acid is the most preferred. The hydrochloric acid salt produces a
crystalline material from several solvents such as 1,4-dioxane,
EtOAc, THF, 2-Me-THF, CHCl.sub.3, CH.sub.2Cl.sub.2, Toluene and
t-BuOH, which are the preferred solvents in this invention. Most
preferred solvent is 2-Me-THF.
[0010] The results of the tests are summarized in the table
below.
TABLE-US-00001 Acid 1,4-Dioxane EtOAc THF 2-Me-THF CHCl.sub.3 HCl
85% 92% 92% 100% 30.4% H.sub.2SO.sub.4 No 76.9% (oil) HNO.sub.3 No
H.sub.3PO.sub.4 * 17.3%.sup. .sup. 17% (oil) (oil) Formic acid
Traces Acetic acid no No No No Benzoic acid No 31.6% Oxalic acid
2.9% 48% 86.5% 81.1% Malonic acid 79.3% Fumaric acid 79% Maleic
acid No (oil) Tartaric acid 36.5% EtSO.sub.3H 106 ** 97% Traces
(oil) p-TosOH No No 93.6% * 0.66 equivalents used ** sticky white
crystals (oil) suspension/colloid/liquefied during isolation
[0011] Should the precipitation of the acid addition salt of
idelalisamine (2) not lead to material of sufficient quality, the
acid addition salt can be recrystallized by methods generally known
in the art. Typical examples of such methods include: allowing a
warm solution of the salt to cool down; allow the solvent of a
solution of the salt to slowly evaporate, and; addition of an
anti-solvent to a solution of the salt.
[0012] In a second aspect the invention relates to acid addition
salts of idelalisamine (2). Preferred acid addition salts of
idelalisamine (2) are the salts of hydrochloric acid, benzoic acid,
oxalic acid, malonic acid, fumaric acid, tartaric acid,
ethanesulphonic acid, or p-toluenesulphonic acid. Most preferred
salt is the hydrochloride salt.
[0013] The salts of this invention can be used as late starting
material for preparing idelalisib (1). Adjustments to the process
as described in WO2005113556 to compensate for the use of the salts
as starting material instead of the free base are routine to the
person skilled in the art.
[0014] The new salts allow substituting one or more of the
chromatographic purification steps in the process of WO2005113556
with purification by precipitation and/or crystallisation in the
idelalisamine stage. Therewith making the process of preparing
idelalisib (1) more efficient on industrial scale from a time and
cost perspective.
[0015] The invention will be further illustrated by the following,
non-limiting, examples.
EXAMPLES
Example 1. Preparation of HCl Salts of Idelalisamine (2) in Various
Solvents
[0016] 0.12 gram (0.357 mmol) of idelalisamine with 88% purity was
dissolved in 3 ml of solvent. 0.032 ml of hydrochloric acid (37%,
0.357 mmol) was added. The mixture was heated to 90.degree. C.
(70.degree. C. for ethylacetate, 35.degree. C. for CH2Cl2) and
allowed to cool down to 0.degree. C. (20.degree. C. for
1,4-dioxane).
TABLE-US-00002 Solvent Yield Purity Ethylacetate 0.110 g (90%)
97.6% Butane-2-ol 0.074 g (62.1%) Toluene 0.062 g (52.0%)
1,4-dioxane 0.101 g (83%) 98.5% THF 0.110 g (91%) 98.8% 2-Me-THF
0.122 g (102%) CH.sub.2Cl.sub.2 0.097 (79%) 97.2%
Example 2. Preparation of Salts of Idelalisamine (2) with Various
Acids in THF
[0017] 0.12 gram (0.357 mmol) of idelalisamine with 88% purity was
dissolved in 3 ml of THF. 0.357 mmol of acid was added. The mixture
was heated to 60.degree. C. and allowed to cool down to 0.degree.
C.
TABLE-US-00003 Acid Yield Ethanesulphonic acid 0.141 g (97%)
Fumaric acid 0.117 g (79%) Sulphuric acid -- Acetic acid -- Benzoic
acid Precipitates at 0.degree. C., dissolves at 15.degree. C.
Nitric acid -- P-toluenesulphonic acid -- Phosphoric acid 0.016 g
(11.4%), liquefies during filtration Oxalic acid 0.066 g (48%)
Maleic acid -- Hydrochloric acid 0.106 g (89%)
Example 3. Preparation of Salts of Idelalisamine (2) with Various
Acids in 2 Me THF
[0018] 0.12 gram (0.357 mmol) of idelalisamine with 88% purity was
dissolved in 3 ml of 2-Me-THF. 0.357 mmol of acid was added. The
mixture was heated to 60.degree. C. and allowed to cool down to
0.degree. C.
TABLE-US-00004 Acid Yield Sulphuric acid 0.108 g (77%), liquefies
during filtration Acetic acid -- Benzoic acid 0.047 g (31.5%)
P-toluenesulphonic acid 0.156 g (94%) Phosphoric acid 0.016 g
(11.4%), liquefies during filtration Oxalic acid 0.119 g (86%)
Maleic acid oil Malonic acid 0.113 g (79%) (2R,3R)-tartaric acid
0.058 g (36.5%)
Example 4. Preparation of Salts of Idelalisamine (2) with Various
Acids in 1,4-Dioxane
[0019] 0.12 gram (0.357 mmol) of idelalisamine with 88% purity was
dissolved in 3 ml of 1,4-dioxane. 0.357 mmol of acid was added. The
mixture was heated to 90.degree. C. and allowed to cool down to
20.degree. C.
TABLE-US-00005 Acid Yield Oxalic acid 0.004 g (3.49%) Acetic acid
--
Example 5. Preparation of Salts of Idelalisamine (2) with Various
Acids in Chloroform
[0020] 0.12 gram (0.357 mmol) of idelalisamine with 88% purity was
dissolved in 3 ml of 2 Me THF. 0.357 mmol of acid was added. The
mixture was heated to 55.degree. C. and allowed to cool down to
0.degree. C.
TABLE-US-00006 Acid Yield Hydrochloric acid 0.030 g (30.4%) Acetic
cid -- Ethanesulphonic acid Liquefies during filtration Oxalic acid
0.093 g (66.9%)
Example 6. Purification of Idelalisamine (2) Via Hydrochloric Acid
Extraction
[0021] 0.442 g (1.383 mmol) of idelalisamine with 93% purity was
dissolved in 10 ml of dichloromethane and extracted with 19 ml of
2% HCl. After separating the layers, the organic phase was
extracted with 6 ml of 1.5% HCl.
[0022] A solution of 50% NaOH was added to the combined aqueous
phases until a pH of approximately 10 was reached. A white
precipitate is formed which is filtered and washed with 5 ml of
water. The product was dried in a vacuum oven at 40.degree. C.
under a pressure of 100 torr with nitrogen stripping for 5
hours.
[0023] Yield: 0.321 g (77%) of white crystals with a purity of
98%.
Example 7. Preparation of tert-butyl
(S)-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbama-
te (3)
[0024] 6.41 g, (14.39 mmol) of compound (4) was dissolved in 55 ml
acetic acid at room temperature. Zinc dust (5.65 g, 86 mmol) was
added in small portions. After each addition, a rise in internal
temperature was observed. The reaction mixture was allowed to cool
below 35.degree. C. before the next portion was added. Addition
took ca. 30 min.
[0025] After 3 hours the reaction mixture was filtered through
celite, the filter cake was washed with a small amount of acetic
acid and the filtrate was concentrated in vacuo.
[0026] The resulting oil was split in ca 7:3 ratio, the smaller
portion was kept for future experiments and the larger portion was
diluted with approximately 20 ml of CH.sub.2Cl.sub.2. The
CH.sub.2Cl.sub.2 solution was filtered through celite to remove
solid material present in the solution and purified by
chromatography using MPLC.
[0027] 2.22 g (5.59 mmol, 55.5%) of compound (3) was isolated.
Example 8. Preparation of Idelalisamine (2) Starting from Purified
(3)
[0028] 2.22 g (5.59 mmol) of compound (3) isolated after column
chromatography as described in example 7 was dissolved in 6 ml of
CH.sub.2Cl.sub.2. 3.82 g (33.5 mmol) of trifluoroacetic acid (TFA)
was added and the reaction mixture was stirred at room temperature
for 5 hours. The reaction mixture was concentrated in vacuo and
partitioned between 10 ml of CH.sub.2Cl.sub.2 and 60 ml of 10%
K.sub.2CO.sub.3. The aqueous layer was extracted with additional
CH.sub.2Cl.sub.2 and the combined organic layers were washed with
water and brine, dried over MgSO.sub.4, filtered, concentrated and
dried in vacuo for 2 hours to result in 1.49 g (5.01 mmol, 89.7%)
of idelalisamine (2) with a purity of 93%.
[0029] Yield starting from compound (4) following examples 7 and 8:
49.7%
Example 9. Preparation of Idelalisamine.HCl (2).HCl Starting from
Crude (3)
[0030] The 0.3 fraction of crude (3) (2.5 g) that was set aside in
example 7 was dissolved in 10 ml of CH.sub.2Cl.sub.2, filtered over
celite and evaporated to dryness to yield 2 gram of an oil.
[0031] 1 gram of this oil was dissolved in 3 ml of
CH.sub.2Cl.sub.2. 0.8 g (7.1 mmol) of trifluoroacetic acid (TFA)
was added and the reaction mixture was stirred at room temperature
for 3 hours.
[0032] The reaction mixture was concentrated in vacuo and
partitioned between 5 ml of CH.sub.2Cl.sub.2 and 20 ml of saturated
NaHCO.sub.3. The aqueous layer was extracted with additional
CH.sub.2Cl.sub.2 and the combined organic layers were washed with
water and brine, dried over MgSO.sub.4, filtered, concentrated and
dried in vacuo for 30 min to result in 0.576 g (1.124 mmol, 95%) of
crude idelalisamine (2).
[0033] This crude material was dissolved in 5 ml of 2-Me-THF and
0.175 ml (2 mmol) of 35% HCl was added. The mixture was stirred at
0.degree. C. for 15 min. and filtered. The residue was washed with
2-Me-THF and dried in vacuo at 40.degree. C. overnight to result in
0.369 g of idelalisamine.HCl (2).HCl with a purity of 98.4% and a
total assay of 79.7%.
[0034] Yield starting from compound (4) following examples 7 and 9:
51.4%.
* * * * *